The gut microbiota plays an important role in cardio-metabolic diseases with diet being among the strongest modulators of gut microbiota composition and function. Resistant dietary carbohydrates are fermented to short-chain fatty acids (SCFAs) by the gut bacteria. Fiber and omega-3 rich diets increase SCFAs production and abundance of SCFA-producing bacteria. Likewise, SCFAs can improve gut barrier integrity, glucose, and lipid metabolism, regulate the immune system, the inflammatory response, and blood pressure. Therefore, targeting the gut microbiota with dietary strategies leading to increased SCFA production may benefit cardio-metabolic health. In this review, we provide an overview of the association between diet, SCFAs produced by the gut microbiota and cardio-metabolic diseases. We first discuss the association between the human gut microbiota and cardio-metabolic diseases, then investigate the role of SCFAs and finally explore the beneficial effects of specific dietary interventions that can improve cardio-metabolic outcomes through boosting the SCFA production.

Background: Acetate is a short-chain fatty acid (SCFA) produced by gut bacteria, which has been implicated in cardio-metabolic health. Here we examine the relationships of circulating acetate levels with gut microbiome composition and diversity and with visceral fat in a large population-based cohort.Results: Microbiome alpha-diversity was positively correlated with circulating acetate levels (Shannon, Beta [95%CI] = 0.12 [0.06, 0.18],P= 0.002) after adjustment for covariates. Six serum acetate-associated bacterial genera were also identified, including positive correlations withCoprococcus,Barnesiella,Ruminococcus, andRuminococcaceae NK4A21and negative correlations were observed withLachnoclostridiumandBacteroides.We also identified a correlation between visceral fat and serum acetate levels (Beta [95%CI] = −0.07 [−0.11, −0.04],P= 2.8 × 10^–4) and between visceral fat andLachnoclostridium(Beta [95%CI] = 0.076 [0.042, 0.11],P= 1.44 × 10^–5). Formal mediation analysis revealed that acetate mediates ∼10% of the total effect ofLachnoclostridiumon visceral fat. The taxonomic diversity showed thatLachnoclostridiumandCoprococcuscomprise at least 18 and 9 species, respectively, including novel bacterial species. By predicting the functional capabilities, we found thatCoprococcusspp. present pathways involved in acetate production and metabolism of vitamins B, whereas we identified pathways related to the biosynthesis of trimethylamine (TMA) and CDP-diacylglycerol inLachnoclostridiumspp.Conclusions: Our data indicates that gut microbiota composition and diversity may influence circulating acetate levels and that acetate might exert benefits on certain cardio-metabolic disease risk by decreasing visceral fat.Coprococcusmay play an important role in host health by its production of vitamins B and SCFAs, whereasLachnoclostridiummight have an opposing effect by influencing negatively the circulating levels of acetate and being involved in the biosynthesis of detrimental lipid compounds.

The optimal dietary pattern to improve metabolic function remains elusive. In a 21-day randomized controlled inpatient crossover feeding trial of 20 insulin-resistant obese women, we assessed the extent to which two isocaloric dietary interventions—Mediterranean (M) and high protein (HP)—improved metabolic parameters. Obese women were assigned to one of the following dietary sequences: M–HP or HP–M. Cardiometabolic parameters, body weight, glucose monitoring and gut microbiome composition were assessed. Sixteen women completed the study. Compared to the M diet, the HP diet was more effective in (i) reducing insulin resistance (insulin: Beta (95% CI) = −6.98 (−12.30, −1.65) µIU/mL, p = 0.01; HOMA-IR: −1.78 (95% CI: −3.03, −0.52), p = 9 × 10⁻³); and (ii) improving glycemic variability (−3.13 (−4.60, −1.67) mg/dL, p = 4 × 10⁻⁴), a risk factor for T2D development. We then identified a panel of 10 microbial genera predictive of the difference in glycemic variability between the two diets. These include the genera Coprococcus and Lachnoclostridium, previously associated with glucose homeostasis and insulin resistance. Our results suggest that morbidly obese women with insulin resistance can achieve better control of insulin resistance and glycemic variability on a high HP diet compared to an M diet.

Objectives: Animal studies support a role for the gut microbiota in hypertension development, but large human studies are lacking. Here, we investigated the relationship between hypertension prevalence and gut microbial composition in two cohorts. Methods: We included 871 unrelated TwinsUK women with faecal microbiome data (16s rRNA gene sequencing). Multivariable linear models adjusted for age, age² and BMI as well as MiRKAT models, were used to estimate the association of hypertension with alpha- and beta-diversity metrics. To identify taxa associated with hypertension, a generalized additive model for location scale and shape was computed adjusting for covariates and multiple testing. Results were replicated in 448 women from PREDICT-1. Results: We found that measures of alpha diversity are significantly lower in hypertensive cases [Beta(95% confidence interval, 95% CI) = −0.05 (−0.095 to −0.004), P = 0.03] and a significant association between beta diversity and hypertension (FDR < 0.05). We identified and replicated two genera associated with hypertension. The genus, Ruminiclostridium 6 was less abundant in hypertension cases [meta-analysis (95% CI) = −0.31 (−0.5 to −0.13), P = 1 × 10⁻³]. The uncultured microbe Erysipelotrichacea-UCG003 was more abundant in hypertensive cases [meta-analysis (95% CI) = 0.46 (0.3–0.62), P = 1 × 10⁻⁴]. We genomically analysed the 16 s rRNA sequence and established a 100% identity match with the 16 s rRNA sequence of the genus Faecalibacillus. We functionally annotated Ruminiclostridium, identifying 83 metabolic pathways, including pathways previously linked to blood pressure regulation. Conclusion: In this large human observation, we show that gut microbiome diversity and composition are associated with hypertension. Our results suggest that targeting the microbiome may be a novel means to prevent or treat hypertension.

Hypertension is the main modifiable risk factor for cardiovascular morbidity and mortality but discovering molecular mechanisms for targeted treatment has been challenging. Here we investigate associations of blood metabolite markers with hypertension by integrating data from nine intercontinental cohorts from the COnsortium of METabolomics Studies. We included 44,306 individuals with circulating metabolites (up to 813). Metabolites were aligned and inverse normalised to allow intra-platform comparison. Logistic models adjusting for covariates were performed in each cohort and results were combined using random-effect inverse-variance meta-analyses adjusting for multiple testing. We further conducted canonical pathway analysis to investigate the pathways underlying the hypertension-associated metabolites. In 12,479 hypertensive cases and 31,827 controls without renal impairment, we identified 38 metabolites, associated with hypertension after adjusting for age, sex, body mass index, ethnicity, and multiple testing. Of these, 32 metabolite associations, predominantly lipid (steroids and fatty acyls) and organic acids (amino-, hydroxy-, and keto-acids) remained after further adjusting for comorbidities and dietary intake. Among the identified metabolites, 5 were novel, including 2 bile acids, 2 glycerophospholipids, and ketoleucine. Pathway analysis further implicates the role of the amino-acids, serine/glycine, and bile acids in hypertension regulation. In the largest cross-sectional hypertension-metabolomics study to date, we identify 32 circulating metabolites (of which 5 novel and 27 confirmed) that are potentially actionable targets for intervention. Further in-vivo studies are needed to identify their specific role in the aetiology or progression of hypertension.

Background: The Dietary Approaches to Stop Hypertension (DASH) diet is beneficial in reducing blood pressure; however, this may be a consequence of concurrent weight reduction. In the present study, we investigated whether body mass index (BMI) mediates the association between the DASH diet and hypertension and investigate common metabolic pathways.Methods: We included 2424 females from the cross‐sectional TwinsUK cohort, with blood pressure, BMI and dietary intake measured within 1.01 (SD = 0.68) years and serum metabolomics profiling (591 metabolites). We constructed a mediation model to test the mediation effects of BMI on the total effect of the DASH diet on hypertension. To identify a metabolite panel associated with the DASH diet and BMI, we built random forest models for each trait, and selected the common metabolic contributors using five‐fold cross‐validation error.Results: We found that BMI fully mediates the association between the DASH diet and hypertension, explaining 39.1% of the variance in hypertension. We then identified a panel of six common metabolites predicting both the DASH diet and BMI with opposing effects. Interestingly, at the univariate level, the metabolites were also associated with hypertension in the same direction as BMI. The strongest feature, 1‐nonadecanoyl‐GPC (19:0), was positively associated with the DASH diet (β [SE] = 0.65 [0.12]) and negatively with BMI (β [SE] = −1.34 [0.12]) and hypertension (odds ratio = 0.71, 95% confidence interval = 0.6–0.84).Conclusions: We highlight the role of BMI in the mechanisms by which the DASH diet influences hypertension and also highlight common metabolic pathways. Further studies should investigate the underlying molecular mechanisms to increase our understanding of the beneficial ways of treating hypertension.